By Arlene WeintraubSep 13, 2021 12:00am
Fierce Pharma’s list of top antibody-drug conjugate contenders includes a mix of Big Pharma players and startups that are expecting major milestones in the coming months. (PDPics/Pixabay)
After Pfizer launched Mylotarg, the first antibody-drug conjugate (ADC) in 2000, it seemed to be the long-awaited “magic bullet” in cancer; it was a drug that would travel straight to tumors and drop a toxic payload inside of them. But despite the excitement and the promise, it took another 11 years for the next ADC (Seagen’s Adcetris) to arrive on the market.
Now, after two decades of trial and error in ADC development, the field is poised to deliver a plethora of targeted drugs to treat a wide range of tumor types. Mylotarg’s initial approval was to treat acute myeloid leukemia, while Adcetris’ was for two types of lymphoma. Now, there are 11 FDA-approved ADCs that are expected to be bringing in more than $20 billion a year in sales by 2030, Evercore ISI estimated in a June report.
In addition, there are more than 50 biopharma companies developing ADCs to treat blood cancers as well as a range of solid tumors, including gynecological, lung and bladder tumors.
“We’re starting to see activity across a number of different solid tumors,” said Maneka Mirchandaney, director of biotech equity research at Evercore ISI, in an interview. “That space has been hard to crack with other modalities, so that’s one of the big differentiating points of [ADC] technology.”
ADCs are constructed with four main elements: a monoclonal antibody designed to target a particular cancer-associated antigen; an anti-cancer medicine as a payload, like a chemotherapy drug; a “linker” that cleaves off that payload inside cancer cells; and the conjugation technology that attaches the linker and payload to the antibody.
But while it sounds relatively straightforward, the construction has been anything but simple for ADC developers. “You need the drug to have an incredible degree of stability as it gets into the tumor,” Mirchandaney said. “You need broad penetration across the tumor, and you need easy release of the payload. Those are really tough problems to solve.”
Mylotarg, in fact, was withdrawn from the market in 2010 after a post-marketing trial raised toxicity concerns. It was reintroduced in 2017 after the FDA cleared it at a lower dose for a subset of leukemia patients.
More recently, the ADC field took a major hit when Sesen Bio received a complete response letter from the FDA for what was expected to be its first product, the ADC Vicineum to treat bladder cancer. A subsequent news report revealed more than 2,000 violations in the company’s pivotal trial. With the future of Vicineum now uncertain, Sesen went from being a top-five contender on this list to being thrown off it altogether.
The Sesen soap opera is a stain on the ADC field, for sure, but it shouldn’t minimize the accomplishments of other companies that have labored for years to improve upon the technology.
“The linker and conjugation technologies especially have meaningfully improved over time,” Mirchandaney said. “With early generations, the drugs dropped off the payloads before they reached tumors, so you got toxicity. The conjugation technology created suboptimal drug properties. But now we have much better linkers and conjugation that can precisely attach the payload to the antibody.”
Advancements in ADC design are already paying off for companies tackling tough-to-treat cancers. Daiichi Sankyo, ranked second on this list, has enjoyed strong demand for its AstraZeneca-partnered ADC Enhertu to treat HER2-positive breast and gastric cancers. Now it’s poised for approval in HER2-mutant non-small cell lung cancer, while also setting out to unseat fourth place Roche and its blockbuster ADC for HER2-positive breast cancer, Kadcyla.
ADCs’ complex design is something that in the long run could actually work to the benefit of their developers, Mirchandaney says. That’s because it will be challenging for biosimilar makers to copy such complex drugs. A lack of biosimilar rivals could translate into greater pricing freedom for ADC pioneers. “What are the prospects for biosimilar development in this space? That’s going to be an important dynamic to watch,” she says.
For this report, Fierce selected a mix of Big Pharma players with established, hit ADCs and startups with strong prospects in their pipelines. What they all have in common is that they’re expecting major milestones in the coming months that could greatly expand their presence in this growing market. Some, like Roche and GlaxoSmithKline, are developing one or two ADCs as part of a diverse oncology strategy. Others are ADC specialists with multiple shots on goal.
The latter group includes our top pick, Seagen. Not only did it nab two bladder cancer FDA approvals this summer for its second ADC, Padcev, but it has one of the deepest ADC pipelines in the industry. As it continues to work towards expanding the markets for Padcev and Adcetris, it’s developing six additional ADCs including disitamab vedotin, a HER2-targeted ADC it recently licensed from China’s RemeGen in a deal worth up to $2.6 billion.
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(National Cancer Institute)
Number of ADCs in pipeline: 8
Estimated sales: $1 billion in 2021, $1.3 billion in 2022
Expected milestones: October 2021 PDUFA for tisotumab vedotin in second-line advanced cervical cancer, plus key data readouts for that ADC in recurrent cervical cancer expected in 2021 and for ladiratuzumab vedotin in triple-negative breast cancer in 2022.
To call Seagen a leader in ADC development would be a bit of an understatement; in July, the FDA handed Seagen and development partner Astellas an earlier-than-expected approval of Padcev for third-line metastatic or locally advanced bladder cancer while also green-lighting it for second-line use in patients ineligible for cisplatin-based chemotherapy. Padcev’s use in bladder cancer alone should eventually push the drug well past blockbuster territory, analysts estimate.
Padcev and Seagen’s other FDA-approved ADC, Adcetris for some patients with Hodgkin lymphoma, are both key players in the company’s burgeoning ADC pipeline. Padcev is being tested in combination with Merck’s immuno-oncology juggernaut Keytruda in bladder cancer and as a solo treatment for advanced solid tumors. Adcetris, meanwhile, is in multiple clinical trials in blood cancers and solid tumors. Evercore ISI estimates sales of the two marketed ADCs will hit $1 billion this year and rise to $1.3 billion next year.
Seagen has six other ADCs under development, including tisotumab vedotin, which could nab an FDA approval in cervical cancer this fall. The latest addition to its pipeline is disitamab vedotin, a HER2-targeted ADC it licensed from China’s RemeGen in a deal worth up to $2.6 billion. Seagen already has a HER2-targeted drug in its portfolio, Tukysa, but the RemeGen deal brings it a potential rival to two high-selling ADCs, AstraZeneca and Daiichi Sankyo’s Enhertu and Roche’s Kadcyla.
“There is competition in the HER2 world, but Seagen has an interesting potential synergistic approach with Tukysa,” said Maneka Mirchandaney, an analyst at Evercore ISI, in an interview. Mirchandaney wrote in a report in June that she believed Seagen has “built a premier ADC R&D engine.”
Seagen’s two-decade path to dominance in ADCs has been anything but smooth. It dabbled in multiple ADC technologies, ultimately throwing out nine failed assets, by Evercore’s calculations, to get where it is today. The company settled on a core technology that uses a valine-citrulline cleavable linker attached to a microtubule disrupting agent that prevents cancer cell division and results in cell death. The linkers are designed to stay stable as they circulate in the body and to release their payload inside cancer cells, a spokesperson for the company explained.
The company’s next big opportunity is cervical cancer, where it’s working with Genmab to develop tisotumab vedotin. Pivotal trial data released last summer in the second-line setting showed that the drug produced a response rate of 24%. The companies are also hoping to crack the third- and first-line cervical cancer treatment settings and the total market opportunity could be nearly $2 billion, Evercore estimated.
Last September, Seagen and Genmab reported that in a phase 2 cervical cancer trial, patients taking tisotumab vedotin had a median survival rate of one year. “Available therapies upon progression after first-line chemotherapy in recurrent or metastatic cervical cancer are limited, and there is a significant unmet need for new treatment options,” chief medical officer Roger Dansey said in an email. He added that responses have been “clinically meaningful and durable” with a safety profile that’s “manageable.”
If tisotumab vedotin is approved in October as expected, that will kick off Seagen’s opportunity in cervical cancer. In the first-line setting for the disease, the company is testing the ADC in combination with several drugs including Keytruda. If it succeeds, the drug could pull in $1 billion a year in cervical cancer just in the U.S., Evercore estimates.
Next year, Seagen could break into another tough-to-crack cancer market, triple-negative breast cancer. Last September, Seagen nabbed $600 million upfront from Merck, which committed to make a further investment of $1 billion to jointly develop the LIV-1 targeted ADC ladiratuzumab vedotin for that market. In addition to moving the drug forward as a solo treatment, the partners are testing it in combination with Keytruda on the hypothesis that the ADC’s cancer-killing effect will boost Keytruda’s effectiveness by drawing activated T and NK cells from the immune system to tumors.
Merck and Seagen reported early data in 2019 showing that 35% of TNBC patients responded to first-line treatment with the ADC-Keytruda combo, though most of those responses were partial. The companies expect to report more data later this year, Dansey said during the company’s second-quarter earnings call.
2. Daiichi Sankyo
Number of ADCs in pipeline: 7
Estimated sales: $550 million in fiscal 2021 (April 2021 to March 2022)
Expected milestones: Readouts from Enhertu head-to-head trial against Roche’s Kadcyla in second-line HER2-positive breast cancer are expected this year and from a second-line HER2-low breast cancer trial in 2022. Potential FDA approval for Enhertu in second-line HER2-mutant non-small cell lung cancer is anticipated in 2022.
Daiichi Sankyo’s antibody-drug conjugate work made a splash in the biopharma world in 2019, when AstraZeneca shelled out a hefty $1.35 billion upfront and committed a whopping $5.55 billion in potential biobucks to license its lead program, trastuzumab deruxtecan.
The drug, now known as Enhertu, went on to snatch an early FDA go-ahead for metastatic HER2-postive breast cancer patients after at least two prior treatments. Wall Street analysts have predicted the drug will bring in $5.7 billion in sales in 2030, betting that it will disrupt the Roche-dominated HER2 market.
Early sales numbers have been encouraging. Between April and June, Enhertu brought in sales of JPY 13.0 billion (about $120 million) worldwide. For Daiichi’s fiscal year that ends next March, the Japanese company expects Enhertu sales to reach JPY 61.0 billion (about $550 million).
Daiichi Sankyo’s ADC platform uses deruxtecan for its drug-linker conjugate. It includes DXd, a potent DNA topoisomerase 1 inhibitor, as the toxic payload, plus a tetrapeptide-based linker to connect it with the antibody drug. In Enhertu’s case, the antibody is trastuzumab, which makes up Roche’s standard-of-care HER2 cancer drug Herceptin and is also the antibody for the Swiss pharma’s own blockbuster ADC, Kadcyla.
Enhertu is widely viewed as a better drug than Kadcyla, with an impressive clinical showing thus far. In the phase 2 Destiny-Breast01 trial, Enhertu shrank tumors in 61% of HER2-postive breast cancer patients who had received a median six lines of prior therapies. The response lasted a median 14.8 months after a median follow-up of 11.1 months. By comparison, Kadcyla triggered a response in 44% of patients, lasting a median 12.6 months in its phase 3.
In January, Enhertu snagged an FDA approval for HER2-positive stomach cancer in patients who previously got Herceptin, after showing it could cut the risk of death by 41% versus chemotherapy in the pivotal Destiny-Gastric01 trial. Kadcyla had previously failed to extend patients’ lives in the same disease setting.
AZ and Daiichi are so confident in outcompeting Kadcyla that the two are pitting Enhertu directly against the Roche drug in second-line breast cancer. Recently headlined results from the phase 3 Destiny-Breast03 trial, reporting that Enhertu beat Kadcyla at staving off tumor progression or death in the second-line setting.
A phase 3 trial of Enhertu in third-line HER2-low breast cancer is on track to read out in early 2022. And AZ and Daiichi have recently launched a trial comparing Enhertu —with or without Roche’s Perjeta—against a combo of Perjeta, Herceptin and chemotherapy in front-line HER2-positive breast cancer. The pair is also testing Enhertu in lung cancer, colorectal cancer and other solid tumors.
The two companies added a second drug to their collaboration last July, when AZ put down $1 billion upfront to license Daiichi’s anti-TROP-2 ADC, DS-1062 (datopotamab deruxtecan), a potential competitor to Gilead Sciences’ Trodelvy. The deal involves up to $5 billion in milestones.
Phase 1 data unveiled at the ESMO Breast Cancer 2021 virtual congress showed DS-1062 shrunk tumors in 43% of triple-negative breast cancer patients who had received a median of four lines of prior therapies.
DS-1062 is currently more advanced in development in non-small cell lung cancer, having recently entered its first pivotal trial in previously treated patients without actional genomic alterations.
Trodelvy also uses a topoisomerase 1 inhibitor for the toxic payload. But Daiichi’s DXd payload is about 10 times more potent, analysts at Evercore ISI noted.
Still, Daiichi’s platform has been linked to the severe side effect of interstitial lung disease, including pneumonitis. The problem may not only complicate the rivalry with Trodelvy, but may also limit Enhertu’s use in earlier lines of breast cancer.
Pharma watchers are looking to detailed results from the Kadcyla head-to-head trial, Destiny-Breast03, to better gauge Enhertu’s safety profile. Interstitial lung disease rates from the study “will have important implications for Enhertu’s potential,” the Evercore ISI team wrote in a recent note.
Daiichi’s long-term ADC pipeline includes U3-1402 (patritumab deruxtecan), a HER3-targeted ADC that has begun pivotal testing for EGFR-mutated NSCLC, as well as a phase 1 trial in that disease combining the ADC with AZ’s megablockbuster EGFR small-molecule inhibitor Tagrisso.
In addition, Daiichi has four other ADCs in development targeting B7-H3, GRP20, CDH6 and TA-MUC1.
There is one cloud hanging over Daiichi’s ADC work: The company and another ADC leader, Seagen, are currently entangled in a legal battle over Daiichi’s ADC technology. Seagen argues that Daiichi infringes upon its patents because the Japanese pharma’s technologies are improvements over the U.S. biotech’s own version and were born from a previous collaboration between the two companies from 2008 to 2015.
3. ADC Therapeutics
Number of ADCs in pipeline: 6
Estimated sales: $23.1 million in 2021, $79.1 million in 2022
Expected milestones: Initiating several trials of recently launched Zynlonta in various combinations to treat B-cell cancers. Data updates also expected on another ADC, camidanlumab tesirine (cami), in Hodgkin lymphoma, along with the start of clinical trials of ADCT-901 in solid tumors.
In April, ADC Therapeutics graduated from R&D outfit to full-fledged commercial biopharma with the approval of its first product, Zynlonta, to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). But as the company’s name indicates, it has much more up its sleeve when it comes to ADCs.
In fact, it has one of the deepest ADC pipelines in the industry. And 2021 should offer investors several hints of how it’s progressing in its effort to expand Zynlonta’s market while at the same time moving the other assets in its pipeline forward.
Zynlonta, a CD19-targeted ADC, was approved based on a phase 2 trial in which it produced a 48.3% overall response rate and 24% complete response rate. The drug generated $3.8 million in sales in its first two months on the market—a respectable showing considering competition from other CD19-targeted treatments such as the personalized CAR-T treatments from Novartis, Gilead Sciences and Bristol Myers Squibb. The consensus expectation among analysts is that the company will finish the year with $23.1 million in sales total and will bring in $79.1 million next year.
Given that Zynlonta’s initial FDA nod is for third-line treatment of DLBCL, the recent approval of Roche’s Polivy in newly diagnosed DLBCL will test ADC’s marketing savvy. Polivy, an anti-CD79b ADC, was already approved in third-line DLBCL but was pulling in meager sales. Now the market for Polivy could be worth up to $3 billion a year, some analysts have suggested.
ADC hopes to set itself apart in the market with its core technology, known as “targeted pyrrolobenzodiazepine (PBD) dimers.” Earlier efforts at PBD-based ADCs failed because the technology seeded proteins that led to resistance. ADC designed its PBDs so they elude DNA-repair mechanisms in cancer cells that typically cause resistance.
The company hopes to expand Zynlonta’s reach and is running multiple studies of the drug in several types of lymphoma.
ADC is also in pivotal trials with a second asset, camidanlumab tesirine (cami), a CD25-targeted drug for Hodgkin lymphoma. In August, the company announced that in a phase 2 trial, the drug produced a response rate of 66.3%.
Investors are certainly optimistic about ADC’s prospects. After backing out of its first attempt at an initial public offering in 2019, the company pulled in $268 million in an upsized offering last year. By August of this year, its shares had traded up to $27, a 42% increase from its IPO.
No doubt investors are betting not just on Zynlonta and cami but also on ADC’s long-term potential with other assets in development. They include ADCs to treat acute lymphoblastic leukemia and solid tumors. So far, cami has generated unimpressive results in solid tumors. Of 44 patients in an early trial with cancers ranging from melanoma to gastrointestinal tumors, none had partial or complete responses and only 11 saw their disease stabilize, prompting Evercore analysts to conclude in a report to investors that targeting CD25 “does not appear to drive a strong enough antitumor response.”
Still, ADC has several shots on goal when it comes to solid tumors. Its long-term pipeline includes ADCs targeting tumor antigens AXL, KAAG1 and DLK1.
Number of ADCs in pipeline: 2
Estimated sales: CHF 2.26 billion ($2.46 billion) in 2021, CHF 2.77 billion ($3.02 billion) in 2022
Expected milestones: Detailed from a phase 3 study of Polivy in front-line diffuse large B-cell lymphoma is expected soon.
Roche may not have developed its own antibody-drug conjugate platform, but by working with other leaders in the field, it became the first to have an FDA-approved product on the market. Now it has two ADCs, along with big plans for both.
Roche’s first ADC, Kadcyla, received the green-light in 2013 for HER2-postive metastatic breast cancer after prior treatment with Roche’s own Herceptin and chemotherapy. Its second ADC, Polivy, won the FDA go-ahead in 2019 for use alongside bendamustine and Roche’s Rituxan in diffuse large B-cell lymphoma (DLBCL) after at least two prior therapies.
Kadcyla was developed with Immunogen’s ADC technology, combining Herceptin (trastuzumab) with the microtubule inhibitor DM1 via a linker dubbed SMCC. For Polivy, Roche tapped into Seagen’s technology, linking the MMAE cytotoxic payload to an antibody targeting CD79b with the mc-vc-PAB linker.
In clinical trials, Kadcyla produced improvements in tumor progression and patient survival over Novartis’ Tykerb-chemo regimen.
Roche tried to bring Kadcyla to newly diagnosed metastatic breast cancer patients, but the ADC didn’t outperform Herceptin and chemo in a phase 3 trial. The company did win an FDA nod in 2019 for Kadcyla as a post-surgery adjuvant treatment for patients with HER2-positive early breast cancer who have residual invasive disease after prior therapy.
The adjuvant indication is fueling Kadcyla’s growth. In the first half of 2021, Kadcyla reeled in global sales of CHF 959 million ($1.05 billion), a 19% year-over-year improvement.
Now ADC leader Seagen has phase 3 trials underway testing whether its small-molecule drug Tukysa, which won FDA approval in breast cancer last April, could be combined with Kadcyla to drive additional benefits.
The biggest competitive threat to Roche is coming from AstraZeneca and Daiichi Sankyo’s rival HER2 ADC, Enhertu. AZ and Daiichi recently reported phase 3 results showing that Enhertu outperformed Kadcyla at preventing tumor progression or death in second-line HER2-positive breast cancer patients.
Analysts predict relatively stable sales for Kadcyla in the next few years. The drug’s annual sales could peak at $2.6 billion from 2021’s expected $2.3 billion and will start to drop in 2026, according to consensus estimates cited by Evercore ISI.
As it tries to drive Kadcyla’s growth, Roche is also gunning for a blockbuster expansion of Polivy. On the same day AZ and Daiichi said Enhertu topped Kadcyla, Roche unveiled phase 3 data showing that a Polivy regimen extended the time to cancer progression or death over the standard-of-care R-CHOP therapy in previously untreated DLBCL. That win made Polivy the first drug in about 20 years to have significantly improved on standard treatment in front-line DLBCL, according to Roche.
As industry watchers have noted, Polivy is taking on an ambitious challenge, as R-CHOP has set a high efficacy bar and has been widely accepted as the standard first-line treatment of DLBCL for nearly two decades. But the reward for winning could be huge. In a July note, Jefferies analyst Peter Welford predicted an additional $3 billion market opportunity for Polivy if the drug’s efficacy benefit is compelling or if there’s a meaningful reduction in side effects. Roche’s pharma chief Bill Anderson has pegged CHF 2 billion sales to the indication.
In third-line DLBCL, Polivy is competing with CD19 CAR-T therapies, namely, Novartis’ Kymriah, Gilead Sciences’ Yescarta and most recently Bristol Myers Squibb’s Breyanzi, as well as ADC Therapeutics’ recently approved Zynlonta. Evercore ISI analysts said it’s still too early to declare a winner between Polivy and Zynlonta, because their respective regimens are different, and they were tested in different trial populations.
Roche is adding Polivy to a combo of Rituxan, gemcitabine and Sanofi’s Eloxatin in relapsed or refractory DLBCL in a phase 3 trial. Other add-on partners that it’s testing include AbbVie-shared Venclexta, and CD20xCD3 bispecific antibodies mosunetuzumab and glofitamab.
Welford’s 2021 sales projection for Roche’s two ADCs was CHF 2.26 billion ($2.46 billion) as of September, with CHF 233 million ($254 million) from Polivy.
5. Gilead Sciences
Number of ADCs in pipeline: 1
Estimated sales: $362 million for Trodelvy in 2021, $788 million in 2022
Expected milestones: The phase 3 TROPiCS-02 readout for Trodelvy in HR-positive, HER2-negative metastatic breast cancer is expected in 2021.
Gilead Sciences joined the antibody-drug conjugate class through its $21 billion acquisition of Immunomedics in 2020. The deal was almost entirely focused on Trodelvy, which RBC Capital Markets analysts predict could reach $4.5 billion in sales by 2030 on a risk-adjusted basis.
Trodelvy delivers DNA topoisomerase inhibitor SN-38 as the toxic payload to tumors expressing TROP-2. Compared with other ADC platforms that typically use an enzymatically cleaved linker, Trodelvy’s CL2A linker is broken down in response to changes in chemical environments.
The ADC won its original FDA nod, an accelerated approval for metastatic triple-negative breast cancer, last April. This April, the company turned its conditional go-ahead into a full one, and the previous mandate for two or more prior therapies before using Trodelvy now only includes one prior round of therapy. Overall, Abrahams predicts that Trodelvy’s metastatic TNBC sales could reach $1.6 billion at its peak.
Breast cancer is Trodelvy’s main battleground, but competition is brewing for the TNBC market among ADCs.
Daiichi Sankyo and AstraZeneca are collaborating to develop their own TROP-2 ADC, datopotamab deruxtecan (DS1062). The toxic payload Daiichi uses, DXd, is about 10 times more potent than SN-38, according to Evercore ISI.
One potential advantage for Trodelvy over datopotamab is that the Daiichi platform has been linked to the serious side effect of interstitial lung disease (ILD). But RBC Capital Markets analyst Brian Abrahams noted in early August that there have been six serious ILD cases reported for Trodelvy in the FDA Adverse Event Reporting System and across the drug’s clinical trials. This could mean “the competitive gap between the drugs may be narrowing,” he suggested.
Nevertheless, Abrahams’ team pointed out the ILD events for Trodelvy remain very rare. And because Trodelvy holds a two-year lead over Daiichi’s ADC, the analyst said Gilead boasts “entrenchment and physician comfort, enabling durable revenues” for Trodelvy.
Yet, there is another competitor on the horizon: Merck has signed on to co-develop Seagen’s anti-LIV-1 ADC candidate ladiratuzumab vedotin, also initially for TNBC. In the drug’s phase 1 trial, it triggered a response in 25% of patients who had received a median of three prior lines of therapy, Evercore ISI analysts noted in a recent report.
Gilead is also trying to expand Trodelvy into HR-positive, HER2-negative disease. The phase 3 TROPiCS-02 trial testing that theory is expected to read out by year-end. The trial is pitting Trodelvy against one of four single-agent treatments per the physician’s choice, including Eisai’s Halaven, an antimicrotubule agent that’s similar to Trodelvy’s payload.
The upcoming data is a “potential inflection point for Trodelvy sales and Gilead stock,” as HR-positive, HER2-neagtive cancers represent about 65% to 70% of breast cancer diagnoses, Abrahams wrote in a June note. While he believes much of Trodelvy’s use will stay in the third-line setting, he still pegged potential $2.2 billion in peak global sales for the indication if the drug was to be successful.
An expert who’s in a relatively large site for TROPiCS-02 pegged the trial as a coin flip, according to Jefferies. The expert noted Halaven has decent efficacy and that prior CDK4/6 treatment might reduce efficacy improvements in both trial arms. Even if Trodelvy hits statistical significance, the drug needs to extend the time patients live without tumor progression by at least one to two months to be clinically meaningful, the expert said. The expert RBC’s Abrahams talked with suggested a progression-free survival difference of about three months would be meaningful efficacy.
In addition to breast cancer, Trodelvy recently snagged an FDA approval in third-line metastatic bladder cancer. There, the drug is mostly viewed as inferior to Seagen’s Nectin-4 ADC, Padcev, given their respective clinical trial performance. Abrahams set $385 million as the indication’s likely peak sales for Trodelvy.
From the two indications, Trodelvy made $89 million in the second quarter, with about 90% from TNBC, Gilead chief commercial officer, Johanna Mercier, said during a call late July.
In an August note, RBC’s Abrahams projected Trodelvy 2021 sales of $362 million and 2022 sales of $788 million on a risk-adjusted basis.
As Evercore ISI noted, Trodelvy is being tested in multiple trials either by the industry or by academia for different TROP-2-related cancer types including breast, bladder, non-small cell lung, head and neck, ovarian and endometrial cancers, among others.
Number of ADCs in pipeline: 1
Estimated sales: $155 million in 2021, $304 million in 2022
Expected milestones: Results from a multiple myeloma trial of a low dose of its approved ADC Blenrep in combination with a gamma secretase inhibitor are expected this year, and data from a trial comparing the drug to standard of care should come within 18 months.
When GlaxoSmithKline won FDA approval for its ADC Blenrep in August 2020, it was both a milestone and a disappointment. The drug, approved for multiple myeloma patients who have failed four previous treatments, was the first to target BCMA, an antigen that’s highly expressed in malignant cells but not healthy tissues. The hope was that focusing on BCMA would reduce the risk of off-target toxicities.
But nearly 75% of patients in the Blenrep clinical trials suffered eye problems, some so serious they led to vision loss. The result: a dreaded “black box” warning on the drug’s label.
Analysts initially predicted Blenrep would reach blockbuster status, but slow pickup is tempering those expectations. The drug brought in £33 million ($45.3 million) in sales last year. GSK reported that first-quarter 2021 sales were £21 million ($28.9 million), and that number stayed flat in the second quarter. That was well below analysts’ estimate of £31 million ($42.7 million) in the second quarter and half of what SVB Leerink’s Geoffrey Porges had been expecting.
When Blenrep was approved, Porges forecast £287 million ($377 million) in 2021 sales and a peak of nearly $2 billion in annual sales. Now he’s estimating the product will bring in around $155 million this year and $304 million next year.
Still, Porges is urging investors not to underestimate Blenrep’s potential, and he’s maintaining his peak sales forecast, at least for now. “Despite these disappointments, GSK has some shots on goal through next year,” he wrote in a note to investors after the second quarter earnings report.
Those include important data readouts from a study comparing Blenrep’s survival benefit to the standard of care for multiple myeloma. And GSK is expecting to report results from a trial that’s combining a gamma secretase inhibitor with a low dose of Blenrep.
“We are investigating a number of strategies to optimize the dosing schedule for Blenrep, and we hope that this substudy will maintain the efficacy of Blenrep but at a lower dose, which could reduce or delay the incidence of ocular events and support the potential use of Blenrep in earlier lines of treatment,” said Hal Barron, M.D., chief scientific officer and president of R&D, during GSK’s July earnings call.
GSK also has several Blenrep combination studies underway in multiple myeloma. They include a phase 3 study in combination with Velcade in the second-line setting and a phase 1 trial of a cocktail of Blenrep, Velcade and Revlimid as a first-line treatment.
Marketing Blenrep will continue to be challenging, however, especially with new BCMA-targeted therapies hitting the market. In March, Bristol Myers Squibb and bluebird bio won FDA approval for their BCMA-targeted CAR-T therapy, Abecma, in patients who had received at least four prior treatments. Johnson & Johnson and Legend Biotech are expecting a verdict for their BCMA-directed CAR-T, cilta-cel, in November.
J&J and Legend nabbed priority review from the FDA based on a trial in which 97% of patients with relapsed and/or refractory multiple myeloma responded to the CAR-T treatment, with 67% showing no signs of cancer after a year. Abecma’s response rate was 72%, with 28% of patients in the pivotal trial having complete remissions. The FDA approved Blenrep based on a trial showing a response rate of 31%, which lasted for more than six months in 73% of responders.
GSK’s executives remain optimistic, though they understand they have their work cut out for them in expanding the market for Blenrep. As Luke Miels, president of global pharmaceuticals said during the earnings call, “we need to address the dosing and … penetrate the earlier lines of treatment, where the vast majority of the opportunity for this product exists.”
7. Mersana Therapeutics
Number of ADCs in pipeline: 4
Estimated sales: N/A
Expected milestones: Updated phase 1 data for lead candidate, upifitamab rilsodotin (UpRi), in ovarian cancer is expected later this year. Top-line phase 1 data for UpRi and XMT-1592 in non-small cell lung cancer are anticipated in the fourth quarter of 2021 and around the end of the year, respectively, and a phase 1 for XMT-1660 and XMT-2056 is expected to start in early 2022.
Mersana Therapeutics has two antibody-drug conjugates locking in on ovarian cancer and non-small cell lung cancer. Its lead candidate, upifitamab rilsodotin, or UpRi, and second-in-line project, XMT-1592, are both targeting NaPi2b, which is widely expressed in those two cancers.
Both ADCs utilize the proprietary DolaLock payload, which contains an auristatin cytotoxic drug. But their ADC platforms are slightly different.
For UpRi, Mersana uses a platform called Dolaflexin. Unlike most other ADCs in which the toxic drug is directly conjugated to an antibody, Dolafelxin attaches the drug molecules to a proprietary biodegradable polymer scaffold, which is then conjugated to the antibody. This increases the number of drug molecules each ADC can carry, which Mersana hopes will lead to better efficacy.
By comparison, XMT-1592 is designed with the Dolasynthen platform, which uses a synthetic scaffold for more precise control of the number of drugs that are tagged onto the antibody, offering more consistent delivery of drugs to cancer cells.
UpRi has shown some effect in ovarian cancer. In a January update of the dose expansion stage of a phase 1 trial, UpRi shrunk tumors in 28% of previously treated patients, and its response rate reached 32% in NaPi2b-high patients. But investors sent the company’s stock price south after the response rates decreased from a previous readout in September 2020. Furthermore, the duration of response was unimpressive at a median of about five months for 10 NaPi2b-high patients. Finally, there was one treatment-related patient death from pneumonitis.
But analysts came to Mersana’s defense. In a note following the data update, BTIG analyst Tom Shrader reminded investors that response durations in heavily pretreated patients are generally short. Both Shrader and SVB Leerink analyst Janathan Chang viewed UpRi’s performance in NaPi2b-high patients as better than the 12% overall response rate historically seen with current standard-of-care chemotherapy.
Mersana has launched Uplift, a single-arm registration trial in platinum-resistant ovarian cancer. For this trial, the company changed how it defines NaPi2b high expression to a TPS score of at least 75. Using the TPS marker, UpRi’s ORR in NaPi2b-high patients in the phase 1 trial improved to 39%.
Roche once had a UpRi candidate called lifastuzumab vedotin (LIFA), which carried a MMAE payload. In a recent note, Evercore ISI pointed out that the now discontinued LIFA showed higher responses when combined with carboplatin, but the neutropenia side effect posed a problem. UpRi showed no grade 3 or higher neutropenia in its own trial, “leaving the opportunity open to combine the drug with platinum-based chemotherapies in earlier line patients,” BTIG’s Shrader wrote in the January note.
For that strategy, Mersana recently launched Upgrade, a phase 1 combination umbrella study. It is initially testing the ADC alongside carboplatin, but other therapies like Avastin, PARP inhibitors or immuno-oncology agents are also on the table, Shrader noted in a report in May.
Later this year, Mersana is expected to provide updated data from UpRi’s phase 1 from the ovarian cancer cohort and plans to report top-line dose expansion results for the NSCLC group.
For XMT-1592, investigators were exploring the right dose in a phase 1 trial as of August. An early NSCLC data readout around the end of the year is possible, Mersana recently said.
Once those data are out, the company will determine which of the two ADCs will move into later-stage NSCLC trials. As Evercore ISI noted in its recent report, XMT-1592 has shown better tumor shrinkage ability than UpRi in animal studies.
During a July conversation with SVB Leerink, Mersana execs acknowledged that NSCLC represents a highly competitive space compared with ovarian cancer and requires setting the response rate bar in a way that’s “future proof,” Chang wrote in a note.
In addition to those two ADCs, Mersana expects to move two preclinical assets into clinical trials in 2022. XMT-1660 is a potential first-in-class ADC against B7-H4. There’s also XMT-2056, developed with Mersana’s Immunosynthen platform. The company plans to disclose XMT-2056’s target later this year.
Number of ADCs in pipeline: 5
Estimated sales: N/A
Expected milestones: Phase 1 data for ABBV-647 and ABBV-011 are expected in 2021.
When we talk about AbbVie and antibody-drug conjugates, it’s hard to ignore the failure of rovalpituzumab tesirine, better known as Rova-T.
Rova-T was designed to deliver a PBD payload to DLL3-expressing small cell lung cancer. The drug was the centerpiece of AbbVie’s buyout of Stemcentrx in 2016. The deal cost AbbVie $5.8 billion upfront and included $4 billion in milestone payments.
Early data in the third-line setting were promising, fanning hopes of a potential speedy approval. But a phase 3 trial in second-line disease quickly went south as Rova-T showed low response rates and performed even worse than traditional chemotherapy topotecan at extending patient life.
Then, a phase 3 flop that tested Rova-T as a maintenance therapy after first-line chemotherapy was the final nail in the coffin for the ill-fated ADC. AbbVie discontinued the drug and took a $5.1 billion write-off related to the Stemcentrx deal in 2018.
Despite the $10 billion loss, AbbVie still has five early-stage ADCs in the works.
Telisotuzumab vedotin, or Teliso-V, is the most advanced ADC program in AbbVie’s pipeline. The drug targets c-Met to deliver the tubulin inhibitor MMAE as the toxic payload. Several c-Met inhibitors have made it to the market to treat non-small cell lung cancer with specific MET mutations—Novartis’ Tabrecta, Merk KGaA’s Tepmetko and AstraZeneca and HutchMed’s Orpathys in China—validating c-Met as a viable target.
Teliso-V has delivered positive phase 2 results as a monotherapy. In the first stage of a registrational phase 2 trial, Teliso-V induced a response in 53.8% of patients with nonsquamous, EGFR nonmutant, c-Met-high tumors. It also showed a response in 25% of patients in the c-Met-intermediate subgroup, according to results unveiled at the AACR 2021 annual meeting. For the EGFR-mutant group, the rate was 13.3% and response was only recorded in those with high c-Met.
The non-squamous EGFR nonmutant subgroup is moving to the trial’s second stage. While the study is continuing to enroll EGFR-mutant patients for the next interim analysis, recruitment into the squamous cohort has stopped because of a lack of efficacy.
Results from the phase 2 program could result in accelerated approval in second-line-plus NSCLC, AbbVie’s president, Mike Severino, told investors during a conference call in April. The company also plans to test the drug in the frontline setting, including in combination with other agents as well as in other c-Met-positive tumor types, he added. In a phase 1 trial, AbbVie paired Teliso-V with AstraZeneca’s EGFR inhibitor Tagrisso, or Roche’s EGFR inhibitor Tarceva or Bristol Myers Squibb’s PD-1 inhibitor Opdivo in NSCLC patients who had run out of options.
Severino also decloaked a second preclinical c-Met ADC candidate, coded ABBV-400, which is expected to enter the clinic this year. The drug uses a topoisomerase inhibitor payload, which Severino said could have greater antitumor efficacy and provide “deeper responses with broader applicability” than other c-Met agents.
Besides the two c-Met programs, AbbVie recently reported preliminary phase 1 data of mirzotamab clezutoclax (ABBV-155) in solid tumors. The drug is an anti-B7H3 antibody conjugated with a BCL-XL inhibitor as the payload. B7H3 is an immune checkpoint that inhibits the tumor antigen-specific immune response.
Two other ADC programs at AbbVie are expected to have early proof-of-concept data this year, according to a pipeline update in February. They include ABBV-011 and cofetuzumab pelidotin (ABBV-647).
A phase 1 trial is testing the SEZ6-targeted ABBV-011 alone or in combination with AbbVie’s own PD-1 inhibitor budigalimab (ABBV-181) in previously treated SCLC.
Cofetuzumab is being developed under a collaboration between AbbVie and Pfizer. The drug is an anti-PTK7 antibody linked to Auristatin-0101, a microtubule inhibitor, and a phase 1 trial is ongoing in patients with PTK7-expressing NSCLC.
Number of ADCs in pipeline: 4
Estimated sales: None in 2021, $36 million in 2022
Expected milestones: Top-line phase 3 data for mirvetuximab soravtansine in platinum-resistant ovarian cancer with high folate receptor-alpha expression are expected in 2021. Top-line data from a registrational phase 1/2 study of IMGN632 in blastic plasmacytoid dendritic cell neoplasm are anticipated in the first half of 2022, while by year-end, the company plans to apply to start a clinical trial for IMGN151.
ImmunoGen’s antibody-drug conjugate technology gave birth to Roche’s HER2-targeting Kadcyla. Though most of the revenue that the biotech is getting these days are royalties tied to Kadcyla sales, the company might soon have a commercial product of its own after a previous failure.
The Massachusetts company is the frontrunner for developing an ADC for ovarian cancer. Its lead candidate, mirvetuximab soravtansine (MIRV), is expected to have phase 3 data in platinum-resistant ovarian cancer with high folate receptor-alpha (FRα) expression in the fourth quarter. The drug links an FRα-targeting antibody with the DM4 payload.
The ongoing phase 3 SORAYA trial isn’t ImmunoGen’s first shot at ovarian cancer for MIRV. Previously, the drug failed in the phase 3 FORWARD I trial with a wider population that also included patients with medium FRα expression levels.
In that study, MIRV failed to top chemotherapy in delaying the time to tumor progression or death. In FRα-high patients, MIRV did cut that risk by about 30%, but the improvement didn’t cross the statistical significance bar thanks to the trial design. What’s more, using a more stringent FRα scoring method called PS2+, ImmunoGen found that 34% of the trial population actually had low FRα expression.
Learning from those lessons, ImmunoGen designed the SORAYA trial such that only FRα-high patients as screened by the PS2+ method are enrolled. It’s a single-arm study that evaluates tumor response rate as the primary goal to support an FDA accelerated approval for second- to fourth-line patients who have been previously treated with Avastin, ImmunoGen CEO Mark Enyedy said during an investor call late July.
The phase 3 trial dubbed MIRASOL will serve as the confirmatory study for the potential accelerated nod. It is pitting the ADC against chemo again in FRα-high, platinum-resistant patients, a group that comprises about 40% of the ovarian cancer market, according to ImmunoGen. That trial also enrolls Avastin-naïve patients to potentially expand MIRV’s use. It could report data in the third quarter of 2022, according to ImmunoGen’s most recent estimate in late July.
Beyond platinum-resistant disease, ImmunoGen is targeting platinum-sensitive patients as well with a new single-arm study called PICCOLO in later-line patients.
The cancer world is heavily invested in combination therapy, and ImmunoGen is no exception. At this year’s ASCO meeting, the company reported positive early data for MIRV coupled with Avastin. The phase 1b FORWARD II trial found the combo triggered a 64% response rate, lasting a median of 11.8 months in patients with high FRα-expressing recurrent ovarian cancer regardless of their platinum sensitivity status.
The FORWARD II trial has other arms examining MIRV pairings with carboplatin, Merck & CO.’s PD-1 inhibitor Keytruda as well as both carboplatin and Avastin.
If SORAYA, MIRASOL, plus the Avastin combo and carboplatin cocktail all succeed, MIRV would be looking at a market of about 8,900 patients per year in the U.S., by ImmunoGen’s estimate. SVB Leerink analyst Jonanthan Chang estimated that MIRV could net $36 million in 2022 sales.
But there are concerns that extended use of PARP inhibitors such as GlaxoSmithKline’s Zejula and AstraZeneca and Merck’s Lynparza in the first-line maintenance setting for patients who respond to initial chemotherapy might affect a patient’s subsequent response to MIRV.
According to Anna Berkenblit, ImmunoGen’s chief medical officer, the “anecdotal data” so far is encouraging. “Throughout our program, when we’ve looked at patients who had a prior PARP inhibitor, whatever trial we look at, we see very nice activity for mirvetuximab,” she said.
In addition to MIRV plans, ImmunoGen expects is to file an investigational new drug application for IMGN151, an anti-FRα ADC.
ImmunoGen has some company in the FRα ADC race. Bristol Myers Squibb recently shelled out $650 million upfront and committed up to $2.5 billion in milestones to secure rights to Eisai’s phase 1 FRα ADC MORAb-202. Sutro Biopharma is also in early clinical development of its lead candidate, dubbed STRO-002.
Also in ImmunoGen’s pipeline is an anti-CD123 ADC for the rare blood cancer blastic plasmacytoid dendritic cell neoplasm (BPDCN). The drug, coded IMGN632, utilizes a conjugation technology called SeriMab, which, according to Evercore ISI, can yield more consistent ADCs with precise number of payloads attached to the antibodies. It also includes the proprietary payload, indolino-benzodiazepine dimers.
The company reached an agreement with the FDA to use a phase 2 study in newly diagnosed and previously treated BPDCN patients for a potential approval. The trial is on track to produce top-line data in the first half of next year.
IMGN632 is also in early-stage testing in combination with Bristol Myers’ Vidaza and AbbVie-Roche’s Venclexta for treating relapsed or refractory acute myeloid leukemia (AML) or as a monotherapy in MRD-positive AML.
There’s also MacroGenics-partnered IMGC936, a first-in-class ADAM9-targeting ADC that’s moving through a phase 1 study in patients with solid tumors that express ADAM9. The drug utilizes SeriMab and a microtubule inhibitor, DM21.
Number of ADCs in pipeline: 1
Estimated sales: NA
Expected milestones: Data from a phase 3 trial of the novel CEACAM5-targeted ADC in advanced NSCLC are expected, and the company has started a basket trial of the drug in breast and pancreatic cancers.
Sanofi made its entry into the ADC arena back in 2003 through a partnership with ImmunoGen. But that pact has seen its share of setbacks. In 2015, Sanofi abandoned an ADC the two were developing against blood cancers. Then in 2017, it retooled the rest of the deal so that it received an exclusive license to develop four of the ADCs they had been working on together.
The company then deep-sixed two of those ADCs, and the status of the third, which was not disclosed in 2017, is now unclear. That leaves just one: tusamitamab ravtansine (formerly SAR408701), nicknamed “tusa” by the company.
Sanofi may not have the deepest ADC pipeline, but if tusa succeeds, it could prove to be one of its most valuable oncology assets. That’s because the ADC is directed at a novel target, CEACAM5, a cancer-driving protein that’s overexpressed in many tumor types but barely occurs at all in normal tissues, potentially offering a new way to attack cancer with minimal side effects.
Tusa is in phase 3 trials as a solo therapy in non-small cell lung cancer. Sanofi also has two phase 2 NSCLC trials underway, one combining the ADC with Merck’s immuno-oncology blockbuster Keytruda and the other testing it alongside Cyramza, Eli Lilly’s VEGFR2-targeted antibody. And the company recently started a basket trial of the drug in other tumors that overexpress CEACAM5.
In a phase 2 study, 20% of NSCLC patients who expressed high levels of CEACAM5 had partial responses to tusa and 42% saw their disease stabilize. Among patients who had previously taken anti-PD1/PD-L1 checkpoint inhibitors like Keytruda, the response rate was 18%.
Analysts won’t be able to estimate tusa’s potential haul before they get a hint of its phase 3 results in NSCLC, and by that time, competition will very likely complicate Sanofi’s marketing task. Several ADCs are in development for NSCLC, including Daiichi Sankyo’s HER2-targeted Enhertu. Other emerging targets in NSCLC include HER3, AXL and TROP2.
Despite its rocky entry into ADC development, Sanofi remains upbeat on its prospects. John Reed, global head of R&D, said during the company’s second quarter earnings call that Sanofi has big plans for tusa. “Tusa aims to not only become the standard of care for patients with CEACAM5 high-expressing tumors in second-line post immunotherapy but also to become the cornerstone of therapy in first-line non-squamous cell lung cancer in combination with a PD-1,” Reed said.